Donepezil, known chemically as (±)-2,3-dihydro-5,6-dimethoxy2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one, is a reversible inhibitor of the enzyme acetylcholinesterase. It is currently available in tablet dosage forms of 5 mg, 10 mg and 23 mg doses under the trade name Aricept® or Aricep® or as orally disintegrating tablets (Aricept® ODT). Aricept® 23 mg film-coated tablet is a sustained-release formulation. Donepezil is indicated for the treatment of dementia of the Alzheimer's type with efficacy established in mild, moderate and severe Alzheimer's disease.
Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by progressive loss of memory and deterioration of higher cognitive functions. In addition to its traditional symptomatology of deficits in cognitive function and memory, AD is characterized by a marked alteration in circadian rhythmicity, beyond that which is associated with ageing. In AD patients, the sleep-wake cycle is more disrupted than in healthy individuals and this can exacerbate behavioral disorders and memory dysfunction.
The sleep-wake cycle comprises three main phases: wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. On the basis of the depth of sleep, NREM sleep is subdivided into stages. In healthy young adults, sleep usually begins at the lightest stage, NREM stage 1, and progresses through stage 2 and into the deepest sleep states, stage 3 and stage 4, also known as delta or slow-wave sleep. The sleeper then progresses back to lighter sleep and then into REM sleep. In healthy individuals, a typical 8-hour period of sleep contains four or five cycles of these alternating sleep phases, with occasional brief awakenings. REM sleep accounts for 20-25% of total sleep time in most human adults.
It is well known that nightmares occur during the REM phase of sleep. The existing donepezil treatment increases the REM sleep percentage and hence causes nightmares.
Sleep disturbances are common in persons with AD. These sleep disturbances include difficulty in falling asleep, multiple awakenings during sleep, disrupted sleep-wake rhythms, and early morning awakenings. Sleep disturbances in persons with AD are a physical and psychological burden for their caregivers and are a major reason why such patients are admitted to long-term care institutions.
ACh plays an important role in maintaining a normal sleep pattern, which is important for memory consolidation. In the brain, ACh is thought to be released from cholinergic neurons according to a circadian rhythm. The cholinergic system is regulated for increased transmission during waking and motor activity and decreased transmission, in general, during sleep, with brief localized increases during REM sleep. The elements of the cholinergic system—synaptic ACh, stored ACh, acetylcholinesterase activity and cholinergic receptors—are coordinated to achieve this end. These rhythms may deteriorate with ageing and is a particular problem in AD.
Behavioral disturbances, such as nocturnal delirium, agitation or wandering are noticeable in older adults with AD and are believed to be associated with disrupted biological rhythms. This phenomenon is called “sundowning” which is a constellation of increasing behavioral disturbances in patients with dementia in the late afternoon or early evening. Sundowning represents an understudied area and the neurobiological basis of this behavioral pattern remains unspecified. One study demonstrates that this behavioral pattern coincides with time-dependent changes in basal forebrain acetylcholinesterase expression.
There exists a need to develop compositions of donepezil which provides reduced incidence of sleep disturbances, which include difficulty in falling asleep, multiple awakenings during sleep, disrupted sleep-wake rhythms and early morning awakenings. There also exists a need to develop compositions of donepezil which reduces the incidence of sundowning. These objectives can be achieved by formulating compositions which release donepezil in a pattern which corresponds with the circadian rhythm of the acetylcholine release from the cholinergic neurons.
The immediate release composition of donepezil results in a spike in the subject's blood plasma levels within 2 to 5 hours after administration of the drug. Following oral dosing, peak plasma concentration is achieved for Aricept® or Aricep® 10 mg, in approximately 3 hours. This initial spike in blood plasma levels causes undesirable side effects in subjects, such as anxiety, nightmares, insomnia, and/or gastrointestinal problems such as nausea, vomiting and diarrhea.
Prior art discloses sustained release compositions as a solution for reducing the incidence of these side effects.
U.S. Patent Application 2005/0232990 discloses a sustained release formulation comprising amorphous donepezil or an amorphous pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymeric carrier, wherein the polymeric carrier maintains the active agent in substantially amorphous form.
U.S. Patent Applications 2006/0280789, 2007/0129402, 2006/0159753, 2009/0208579, and 2011/0045074 disclose orally administrable matrix type sustained release formulations comprising a basic drug, an enteric polymer, and, optionally, one or more compounds selected from water-insoluble polymers, water-soluble sugars, sugar alcohols, and pharmaceutically acceptable excipients.
U.S. Patent Applications 2008/0213368 and 2010/0152164 disclose pharmaceutical compositions containing an anti-dementia drug and sustained-release base, with storage stability of the anti-dementia drug, wherein a high molecular weight acidic substance is added for stabilizing the anti-dementia drug.
PCT Application WO 2011/069076 discloses a sustained release tablet formulation comprising donepezil or a pharmaceutically acceptable salt thereof, further comprising at least one release rate controlling material that is a hydrophilic material, hydrophobic material, enteric polymer, or any combination thereof.
U.S. Patent Application 2011/0218216 discloses an extended-release pharmaceutical composition for an oral administration comprising donepezil or pharmaceutically acceptable salt thereof, a release-controlling agent and a microenvironment pH modifier.
U.S. Patent Application 2011/0237623 discloses a sustained-release formulation for an acetylcholinesterase inhibitor, comprising an acetylcholinesterase inhibitor and at least two gel-forming polymers.
However, the label of Aricept® or Aricep® discloses that the gastrointestinal side effects (nausea, vomiting and diarrhea), when they occur, appear more frequently with the 10 mg/day dose than with the 5 mg/day dose and more frequently with the 23 mg dose (sustained release formulation) than with the 10 mg dose. Specifically, in a controlled trial that compared a dose of 23 mg/day to 10 mg/day in patients who had been treated with donepezil 10 mg/day for at least three months, the incidence of nausea in the 23 mg group was markedly greater than in the patients who continued on 10 mg/day (11.8% vs. 3.4%, respectively), and the incidence of vomiting in the 23 mg group was markedly greater than in the 10 mg group (9.2% vs. 2.5%, respectively). The percent of patients who discontinued treatment due to vomiting in the 23 mg group was markedly higher than in the 10 mg group (2.9% vs. 0.4%, respectively).
Public Citizen, representing more than 225,000 members and supporters nationwide, had petitioned to the US FDA in June 2011 to immediately remove the 23 mg dose of Aricept® from the market because the 23 mg dose of Aricept® failed to meet the two efficacy criteria required by FDA as a condition of approval of drugs for dementia, and because the 23 mg dose of Aricept® significantly increased adverse events compared to the previously approved 10 mg dose, including increased risks for nausea, vomiting, diarrhea, anorexia, and confusion.
Hence, there is still a need for developing compositions of donepezil which provide a reduced incidence of undesirable gastrointestinal side effects in subjects, which include nausea, vomiting and diarrhea.